In the nervous system, both the number and the multipotency of neural stem cells (NSCs) decrease during aging. The depletion of NSCs may undertie the age-dependent decline in cognitive function. Understanding the mechanisms that maintain functional stem cells in adulthood will help identify ways to preserve the NSC reservoir during aging. Our lab has characterized the molecular mechanisms of action of specific genes that play a central role in organismal aging, in particular Foxo transcription factors. We have recently discovered that Foxo3, a member of the Foxo family of transcription factors associated with extreme longevity in humans, regulates the maintenance of adult NSCs in vivo in mice and multipotency of these cells in culture. We have identified a program of genes regulated by FoxoS in NSCs. A molecular pathway common to organismal aging and stem cell biology may help to explain why the number and function of adult NSCs decrease with age. Our specific hypothesis is that FoxoS maintains the homeostasis of NSCs in young adults, by triggering a specific program of gene expression in these cells, and that this program is progressively altered during aging. To test this hypothesis, we propose the following specific aims: 1. To examine the importance and the regulation of FoxoS in aging NSCs 2. To understand the mechanisms of action of FoxoS in NSC homeostasis 3. To explore how FoxoS regulates epigenetic changes in aging NSCs A combination of genetic, molecular, and genomic approaches will be used to develop these aims. The ability of FoxoS to regulate the NSC pool may be pivotal for preserving cognitive function during aging in mammals. Investigating the molecular mechanisms that undedie adult NSC homeostasis should also provide key insights into the limitations preventing regeneration in the aging nervous system. RELEVANCE (See instructions): As the organism ages, adult neural stem cells (NSCs) are depleted. Adult NSCs have recently been found to be important for learning and memory, raising the intriguing possibility that the maintenance of an intact NSC pool may help preserve cognitive function with advancing age. Uncovering the mechanisms underlying the adult NSC maintenance should give important insights into the factors that control regeneration in the normal aging nervous system as well as in age-related neurodegenerative diseases.